Persistence in allergen immunotherapy: A longitudinal, prescription data‐based real‐world analysis

Abstract Introduction Allergic rhinitis (AR) is a widespread disease with increasing prevalence in developed countries. The only treatment that tackles the underlying causes is allergen immunotherapy (AIT). This treatment is performed through two application routes, the subcutaneous immunotherapy (SCIT) or the sublingual immunotherapy (SLIT). However, persistence during the long course of treatment over 3 years is key for the efficacy of this treatment option. The impaired adherence significantly impacts public health resources. The aim of this study was to assess the persistence of AIT for both application routes. Methods IQVIATM LRx was used to identify patients starting AIT between 2009 and 2018 with grass pollen (GP), early flowering tree pollen (EFTP) and house dust mite (HDM) allergens. Patients were classified within each allergen category by AIT groups (subcutaneous depigmented polymerised allergen AIT [dSCIT], other subcutaneous AIT [oSCIT] and SLIT) and age (5‐11 years, 12‐17 years, 18+ years). Furthermore, they were followed up for up to 3 years until the cessation of treatment. Patients, who were still on treatment after 3 years were deemed to be censored. Kaplan‐Meier curves of persistence were generated and compared by log‐rank tests. Results The number of patients included in the three allergen categories was 38,717 GP, 23,183 EFTP, and 41,728 HDM AIT. In all allergen categories and for any product group, patient persistence decreased with increasing age class with the difference between 5‐11 years and 12‐17 years greater than between the latter and 18+ years. The percentage of patients completing the first year of AIT was low, particularly for SLIT where 22.2%–27.1% of patients remained persistent after 12 months. The equivalent figures for dSCIT were 52.0%–64.1% and for oSCIT 38.3%–50.3%. Conclusion Persistence in AIT in AR was low in this retrospective prescription‐based database and was clearly linked to patient age and application route.


| INTRODUCTION
Allergic rhinitis (AR) is a common medical complaint, particularly in developed countries where prevalence can reach up to 20% of the population. 1,2 The three main allergen triggers are grass and early flowering tree pollen as well as house dust mites. If uncontrolled, AR is known to be a distinct risk factor for the development of allergic asthma; conversely, up to 80% of asthmatic patients also suffer from AR. 3 Medical treatment is usually symptomatic, 4 encompassing for example, antihistamines or anti-inflammatory nasal steroids.
Allergen immunotherapy (AIT) is the only causal and preventive disease-modifying therapy available. [5][6][7] By repeatedly exposing the patient to an allergen, the immune system develops tolerance to allergen exposure. For AIT, several standardized products are available, differentiated by the route of application as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). For SCIT, unmodified allergens or chemically modified allergens (allergoids) are used. 6 SLIT, on the other hand, is mostly available in the form of unmodified allergens. SCIT is administered by a physician and requires regular visits, whereas SLIT is administered by a patient at home without further supervision. AIT is usually indicated in patients over 5 years of age and can be applied at any age. It is generally accepted that an early introduction to AIT is desirable for this to provide a complete and long-lasting improvement. 6 Patient adherence to the treatment regimen and persistence is essential for efficacy of AIT. Patients should be treated for at least 3 years. [4][5][6][7] Other factors increasing the efficacy of AIT include early initiation after the onset of AR, minor affliction of the lower airways at the time of initiation, young patient age, and a high cumulative AIT dose. 6 Common problems with AIT include poor adherence and premature termination, which happens more often in SLIT-treated subjects. [8][9][10] AIT products show a good safety profile. Efficacy of AIT has been demonstrated in a large number of double-blind placebo controlled (DBPC) studies, which demonstrate and quantify their effects under standardized clinical conditions. This laid the path for several AIT guidelines. 11 Numerous trials provide strong evidence for the efficacy of SCIT in pollen and mite allergy-induced allergic rhinoconjunctivitis in adulthood; however, only a limited number of studies in children and adolescents have been performed. 5,6 Up to date, the European Medicines Agency's applicable principles on study design and efficacy claims, request the DBPC randomized trial design. 12,13 Controlled studies feature inherent results bias since patients included are selected according to clearly defined inclusion and exclusion criteria and are instructed and monitored during the course of the study. [14][15][16] Therefore, the results of randomized controlled trials (RCTs) are only representative of about 5% of the general population, which differs in characteristics such as BMI, comorbidities, or age. 17 Consideration of the heterogeneity of the population and evidence of reliable real-world evidence (RWE) studies are therefore essential to assess the efficacy and safety of AIT under real-world conditions. RWE aims to support RCT evidence by analysing data from daily clinical practice. This approach has been demonstrated to be very helpful, reliable, and complementary to controlled trials in the field of AIT, especially allowing insights into effectiveness in children and adolescents. 9,18,19 This RWE study aimed to analyse large data on longitudinal prescriptions for SCIT and SLIT over three continuous years of treatment to obtain deeper insight into the persistence rates of patients receiving SCIT and SLIT.

| METHODOLOGY
The database used for the analyses was IQVIA TM LRx which is based on prescription data of statutorily insured patients in Germany. The panel used here covers 60% of the German statutory population. Fully anonymized data is available at the patient level and include demographic information (age, sex) and all information related to prescriptions (product, substance, form, package size, etc.). There is no data available for diagnoses and Within each group, patients were selected if they satisfied the following criteria: � Initial prescription in allergen-specific selection timespan (no AIT in the previous 560 days). The product and prescription date were designated as the index product and the index date respectively.
� Patient aged ≥5 years at index date.
The following three product groups were defined and analysed: � Depigmented polymerized allergen extract (dSCIT).
For each prescription, the application duration was estimated using the manufacturer's recommendation. For subcutaneous treatments, the duration was based on the total package volume and volume per application considering differential application volumes during updosing. Pre-seasonally treated SCIT patients were removed from the analyses. Patients were observed until the first of the following occurred: � Complete cessation of index product AIT.
� Grace period (end to next start of successive prescriptions) in index product AIT exceeding 90 days.
� Switch to non-index product AIT in the same allergen category.

� End of patient observability
Patients with the first three events were deemed to be nonpersistent, and patients with the last were censored. Kaplan-Meier curves of persistence were derived for each AIT group over the first three years (1095 days) after the index. The analyses were always stratified by allergen category and product group and were conducted for the overall group as well as by age class at index (children: 5-11 years, adolescents: 12-17 years, adults: 18+ years).
Persistence quartiles and mean persistence within the 3 year analysis timespan were calculated and grouped persistence curves compared by log-rank tests. For comparisons involving more than two groups, a Bonferroni correction was used to maintain the overall p-value at 5% (p < 0.05). The software used for the analyses was SAS 9.4. Within the AIT group and based on a combination of parameters (mean and median persistence, persistence at 1 and 3 years), each AIT group performed best in different allergen categories: for dSCIT, the highest persistence was found in the EFTP category, for oSCIT in the GP category and for SLIT in the HDM category (Table 1) In all allergen categories and for all AIT groups, the highest persistence was recorded for children, followed by adolescents and adults (  comparisons within an allergen category between AIT groups and between age classes within an AIT group were highly significant (p < 0.0001) except between the two SCIT groups in the GP category (p = 0.1534) and between the age classes for SLIT in the EFTP (significant only for children vs. adolescents) and the HDM (not significant for adolescents vs. adults) categories (Table 3).

| DISCUSSION
The expected duration of AIT is 3 years even though a longer treatment duration is possible and many manufacturers' recommendations state that application should be 3-5 years. 6 In our real-world study, overall persistence across all allergen categories and AIT groups was low and decreased gradually over the entire analysis timespan, particularly after the first year. There are various possible reasons for treatment cessation, including strong side effects, lack of efficacy, or spontaneous contraindication (e.g. pregnancy in women). 8 Due to the current study design, it was not possible to define the reasons for the lack of persistence.
Our results are in line with former data from another retrospective analysis based on a Dutch community pharmacy database of 6486 patients receiving SCIT or SLIT. 10 This analysis also found a low persistence in AIT with only 18% of patients reaching the full treatment course of 3 years (23% in SCIT patients, 7% in SLIT patients). The persistence rates are even lower than those ones T A B L E 2 Statistics for persistence of the product groups separated by allergen category and age class.  In addition, distinctions between the age classes were also found with children having consistently the highest persistence, followed by adolescents and finally adults. Medical treatment of children is regularly supervised by their parents so that the higher persistence rates of this age class are expected, and a strong correlation here has been recorded. 22 With regard to adolescents, it is known that adherence to medicinal therapy is low in this age class in general and often even poorer than that of adults. This phenomenon was not seen here with adolescent persistence generally on a par with or even a little higher than that of adults. The low persistence of adults on AIT seems paradoxical at first sight, implying a less responsible attitude with respect to medical therapy than even that of adolescents. However, it is generally recognized that AIT is more efficacious in young patients. This might negatively impact the persistence of adults. Many reviews could not find a positive correlation between age and implementation of treatment regimen. 22 Our results clearly demonstrate that SCIT patients performed better than SLIT-treated individuals. Although it should be considered that oSCIT consisted of a mixture of products, which do not show similar persistence, the differences between dSCIT and oSCIT were substantial in all three allergen categories. It is known that SLIT application leads to a higher rate of milder but discomforting side effects such as oromucosal pruritus or gastric discomfort, especially during the first weeks of therapy. 5,6,23,24

| LIMITATIONS
The main limitation of the database with respect to the current investigation is the lack of prescription posology information which is crucial in determining the duration of a prescription. Since all other prescription information (allergen, starter/maintenance form, package size, count, etc.) was available, it was possible to make reliable estimates using the recommended application regimes of the manufacturers. This was particularly the case for SLIT where these regimes are rigidly fixed. Any remaining dosage uncertainties were minimized by the fact that prescription overlap (signifying overuse) was ignored and short pauses between prescriptions (signifying underuse) were tied over by means of the grace period.

| CONCLUSIONS
Persistence on AIT therapy in the three allergen categories assessed was distinctly higher for SCIT than for SLIT. Children showed consistently higher persistence than both adolescents and adults.
Nevertheless, the persistence of all groups analysed under real-world conditions was low and it is likely that treatment intensity in a substantial proportion of patients was too low to exert efficacy. It would be desirable to elucidate the reasons for low AIT persistence to take proper measures wherever possible. Improving strategies for optimizing adherence to AIT poses one of the most relevant aims for future developments in AIT.

AUTHOR CONTRIBUTION
Oliver Pfaar and Angelika Sager proposed the study, analysed the data and wrote the paper in collaboration with Hartmut Richter (IQVIA). Hartmut Richter performed the analysis and wrote the first draft of the paper in collaboration with AS and Oliver Pfaar. Christoph Miller, Thomas Müller and Marek Jutel participated in the discussion of the results and contributed to the paper. All authors agreed to its publication.